Experiments of this proposal will examine how exercise training affects regulation of nitric oxide in coronary collaterals developed in response to chronic coronary occlusion in miniature swine. Five specific aims are proposed to systematically evaluate the effects of chronic exercise on various cellular biochemical events necessary for nitric oxide production: 1) Regulation of nitric oxide by changes in intracellular calcium will be examined; 2) the synergism between angiogenic growth factors, vascular endothelial growth factor (VEGF), and basic fibroblast growth factors (bFGF) and endothelial function will be examined; 3) regulation of superoxide dismutase will be evaluated to determine how production of superoxide radicals may relate to the bioavailability or stability of nitric oxide; 4) regulation of plasmalemmal caveolae microdomains will be examined; 5) these various aspects of control of nitric oxide (Specific Aims 1-4) will be compared between vessels derived from male and female animals. Results of these experiments will identify underlying endothelial mechanisms and sites of action which may implicate potential new therapeutic directions for optimizing blood flow to collateral-dependent myocardium distal to a chronic coronary artery occlusion in patients with coronary artery disease.